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Written by Peng Zhixin, edited by Peng Zhixin, Wang Sizhen Depression is a serious mental illness that is widespread in all ages and suffers from a large number of patients.
Depression can significantly increase the risk of suicide and induce physical illness [1-4]
.
Previous studies have reported that neuroinflammation is a risk factor for mood disorders, especially in patients with depression, neuroinflammation has been observed, including the release of activated microglia and inflammatory mediators [5,6]
.
Dlg1 gene has been reported to play an important role in neuronal synapses, tumorigenesis, peripheral immune cell activation and proliferation [7-9], but its function in microglia activation and neuroinflammation is still unclear
.
On September 6, 2021, the joint team of Professor Yuan Zengqiang from the Academy of Military Medical Sciences and Associate Professor Cheng Jinbo from Minzu University of China published an online publication entitled "Dlg1 Knockout Inhibits Microglial Activation and Alleviates Lipopolysaccharide-induced Depression-like Behavior in Mice" on the Neuroscience Bulletin.
"The research paper reveals the important role of Dlg1 in the activation of microglia and provides a potential therapeutic target for neuroinflammation-mediated depression
.
Master Peng Zhixin from Nanhua University and Dr.
Xiaoheng Li from the Academy of Military Medicine are the co-first authors of the paper
.
(See also "Logical Neuroscience" Yuan Zengqiang/Cheng Jinbo's latest research report: Sci Adv︱ Important Discovery! Calcium Homeostasis Regulatory Protein Calhm2 Regulates Microglial Cell Activation and Participates in the Process of Alzheimer's Disease) Microglial Cell Mediation Leading neuroinflammation is widely considered to be an important cause of many neurological diseases and mental disorders (including depression) [3,4]
.
Discs large homolog 1 (Dlg1 for short) belongs to the family of related guanylate kinases.
As an adaptor protein, it participates in regulating cell polarization and K+ channels.
At the same time, K+ channels play an important regulatory role in the activation of microglia [ 10, 11]
.
However, the role of Dlg1 in the maintenance of microglia and central nervous system homeostasis is unclear
.
In this study, the researchers first established a BV2 cell line with Dlg1 knockdown or overexpression in vitro, and treated it with LPS (an inducer widely used for microglia activation) to study the effect of Dlg1 in microglia.
It was found that the release of pro-inflammatory cytokines was significantly reduced after the Dlg1 gene of BV2 cells was knocked down; the corresponding results of overexpression cell lines were significantly increased (Figure 1), suggesting that Dlg1 is involved in microglia Activation process
.
Figure 1 Knockout of Dlg1 gene in microglia inhibits LPS-induced inflammation (picture quoted from: Z Peng, et al.
, Neurosci Bull 2021) Previous studies have confirmed that LPS is an activator of NF-κB and MAPK pathways [12 , 13], therefore, the researchers used a short-term LPS stimulation and found that the phosphorylation levels of various pathway proteins in the Dlg1 knockout BV2 cells were significantly reduced, including p-IKKα/β, p-IκBα, p-JNK and p-P38
.
Correspondingly, overexpression of Dlg1 significantly increased the levels of these proteins
.
In addition, in order to determine whether Dlg1 depends on the activity of potassium channels to regulate microglia-mediated inflammation, the researchers applied a series of potassium channel culture fluids with a concentration gradient to inhibit the activity of potassium channels, and found that it is regulated by Dlg1 gene knockout The decreased levels of p-Ikka/b, p-JNK and p-P38 decreased with the increase of K+ concentration; the levels of inflammatory cytokines TNF-α and IL-6 were also significantly suppressed (Figure 2), suggesting Dlg1 By targeting NF-κB and MAPK pathways, it participates in the activation of microglia and its mediated inflammation, which may partly depend on potassium channel activity
.
Figure 2 Dlg1 regulates the NF-κB signaling pathway in microglia (picture quoted from: Z Peng, et al.
, Neurosci Bull 2021) Since Dlg1 gene knockout significantly reduces the inflammatory response of microglia, the researchers Try to explore the role of Dlg1 in inflammation-induced depression
.
The researchers first established mice (Dlg1flox/flox; CX3CR1CreER, referred to as cKO mice) that could induce microglial cell-specific Dlg1 gene knockout, and used tamoxifen to induce Cre recombinase activity in microglial cells.
To achieve the purpose of knocking out Dlg1
.
Then LPS (1mg/kg) was injected intraperitoneally to induce depression-like behavior in mice
.
The analysis of the behavioral test results of mine test, elevated plus maze, tail suspension test, and forced swimming test found that the lack of microglia Dlg1 can reduce inflammation-induced depression-like behavior in mice (Figure 3)
.
Figure 3 Knockout of Dlg1 gene in microglia can alleviate depression-like behaviors in mice induced by LPS (picture quoted from: Z Peng, et al.
, Neurosci Bull 2021) The morphology and number of microglia in the brain were studied, and the results of immunofluorescence and immunohistochemical staining showed that the Dlg1 gene knockout of microglia significantly saved the number and length of microglia branches induced by LPS.
Decrease and increase in cell body area
.
In addition, LPS injection increased the number of microglia in the hippocampus of control mice, while Dlg1 conditional gene knockout of microglia significantly reduced this increase (Figure 4)
.
These results indicate that the Dlg1 gene knockout in microglia significantly inhibits the activation of microglia in the mouse brain
.
Figure 4 Knockout of Dlg1 gene in microglia prevents the activation of microglia in vivo (picture quoted from: Z Peng, et al.
, Neurosci Bull 2021) Finally, the researchers analyzed iNOS, IBA1 and GFAP proteins in mouse hippocampus The protein levels of iNOS and IBA1 in cKO mice were significantly reduced under the stimulation of LPS, and the levels of GFAP decreased compared with control mice.
Inflammation of cKO mice Sex cytokines TNF-α and IL-6 were significantly reduced, and IL-1β levels showed a downward trend (Figure 5)
.
Together, these results indicate that the conditional deletion of Dlg1 by microglia inhibits the activation of microglia, thereby reducing depression-like behaviors caused by neuroinflammation
.
Figure 5 Knockout of Dlg1 gene in microglia can reduce inflammation in the brain of mice (picture quoted from: Z Peng, et al.
, Neurosci Bull 2021) Conclusion and discussion, inspiration and prospects of the article In summary, the study shows Knockout of Dlg1 gene inhibits the activation of NF-κB signal and MAPK pathway in microglia, thereby reducing the activation of microglia and the release of pro-inflammatory cytokines
.
In addition, the deletion of Dlg1 gene in microglia can alleviate depression-like symptoms in mice induced by inflammation
.
At the same time, the relationship between Dlg1 and potassium channel activity in this study is not clear, and whether it plays a synergistic effect in the disease process still needs further research
.
In conclusion, this study reveals the important role of Dlg1 in the activation of microglia and provides a potential therapeutic target for the treatment of depression
.
Original link: https://doi.
org/10.
1007/s12264-021-00765-x The corresponding author of this paper is Associate Professor Cheng Jinbo of Minzu University of China, and Researcher Yuan Zengqiang of the Academy of Military Medicine
.
The first author is Peng Zhixin from Nanhua University and Dr.
Li Xiaoheng from the Academy of Military Medicine
.
This work was greatly helped by Professor Liu Wanli of Tsinghua University
.
This work was jointly funded by key projects of the National Natural Science Foundation of China and general projects
.
Selected articles from previous issues [1] JAMA Neurol︱ Attention! Young people are more likely to suffer from "Alzheimer's disease"? [2] Brain | For the first time! PAX6 may be a key factor in the pathogenesis of Alzheimer's disease and a new therapeutic target [3] Sci Adv︱ blockbuster! DNA methylation protein DNMT1 mutation can induce neurodegenerative diseases [4] Cell︱ new discovery! New enlightenment of midbrain-regulated movement phenomenon for the treatment of Parkinson’s disease [5] Cereb Cortex︱MET tyrosine kinase signal transduction timing abnormality is a key mechanism affecting the development and behavior of normal cortical neural circuits in mice [6] Nat Biomed Eng︱ The team of academician Ye Yuru develops a new strategy for whole-brain gene editing-mediated treatment of Alzheimer's disease [7] Luo Liqun Science's heavy review System interpretation ︱ Neural circuit structure-a system that makes the brain "computer" run at high speed [8] Sci Adv ︱Important discovery! The calcium homeostasis regulatory protein Calhm2 regulates the activation of microglia and participates in the process of Alzheimer's disease [9] EMBO J︱ new discovery! AGHGAP11B promotes the expansion of the neocortex into adulthood and improves cognitive ability [10] Cell Death Differ︱ Qi Yitao/Wu Hongmei and others cooperate to reveal the molecular mechanism of SUMO modification regulating neurogenesis in adult mice [11] Cereb Cortex︱A2A receptor antagonist can Reversal of sequence learning impairment induced by abnormal aggregation of α-Syn (slide up and down to view) [1] ANDRADE L, CARAVEO-ANDUAGA JJ, BERGLUND P, et al.
The epidemiology of major depressive episodes: results from the International Consortium of Psychiatric Epidemiology (ICPE) Surveys [J].
International journal of methods in psychiatric research, 2003, 12(1): 3-21.
【2】CHENG AT, CHEN TH, CHEN CC, et al.
Depression can significantly increase the risk of suicide and induce physical illness [1-4]
.
Previous studies have reported that neuroinflammation is a risk factor for mood disorders, especially in patients with depression, neuroinflammation has been observed, including the release of activated microglia and inflammatory mediators [5,6]
.
Dlg1 gene has been reported to play an important role in neuronal synapses, tumorigenesis, peripheral immune cell activation and proliferation [7-9], but its function in microglia activation and neuroinflammation is still unclear
.
On September 6, 2021, the joint team of Professor Yuan Zengqiang from the Academy of Military Medical Sciences and Associate Professor Cheng Jinbo from Minzu University of China published an online publication entitled "Dlg1 Knockout Inhibits Microglial Activation and Alleviates Lipopolysaccharide-induced Depression-like Behavior in Mice" on the Neuroscience Bulletin.
"The research paper reveals the important role of Dlg1 in the activation of microglia and provides a potential therapeutic target for neuroinflammation-mediated depression
.
Master Peng Zhixin from Nanhua University and Dr.
Xiaoheng Li from the Academy of Military Medicine are the co-first authors of the paper
.
(See also "Logical Neuroscience" Yuan Zengqiang/Cheng Jinbo's latest research report: Sci Adv︱ Important Discovery! Calcium Homeostasis Regulatory Protein Calhm2 Regulates Microglial Cell Activation and Participates in the Process of Alzheimer's Disease) Microglial Cell Mediation Leading neuroinflammation is widely considered to be an important cause of many neurological diseases and mental disorders (including depression) [3,4]
.
Discs large homolog 1 (Dlg1 for short) belongs to the family of related guanylate kinases.
As an adaptor protein, it participates in regulating cell polarization and K+ channels.
At the same time, K+ channels play an important regulatory role in the activation of microglia [ 10, 11]
.
However, the role of Dlg1 in the maintenance of microglia and central nervous system homeostasis is unclear
.
In this study, the researchers first established a BV2 cell line with Dlg1 knockdown or overexpression in vitro, and treated it with LPS (an inducer widely used for microglia activation) to study the effect of Dlg1 in microglia.
It was found that the release of pro-inflammatory cytokines was significantly reduced after the Dlg1 gene of BV2 cells was knocked down; the corresponding results of overexpression cell lines were significantly increased (Figure 1), suggesting that Dlg1 is involved in microglia Activation process
.
Figure 1 Knockout of Dlg1 gene in microglia inhibits LPS-induced inflammation (picture quoted from: Z Peng, et al.
, Neurosci Bull 2021) Previous studies have confirmed that LPS is an activator of NF-κB and MAPK pathways [12 , 13], therefore, the researchers used a short-term LPS stimulation and found that the phosphorylation levels of various pathway proteins in the Dlg1 knockout BV2 cells were significantly reduced, including p-IKKα/β, p-IκBα, p-JNK and p-P38
.
Correspondingly, overexpression of Dlg1 significantly increased the levels of these proteins
.
In addition, in order to determine whether Dlg1 depends on the activity of potassium channels to regulate microglia-mediated inflammation, the researchers applied a series of potassium channel culture fluids with a concentration gradient to inhibit the activity of potassium channels, and found that it is regulated by Dlg1 gene knockout The decreased levels of p-Ikka/b, p-JNK and p-P38 decreased with the increase of K+ concentration; the levels of inflammatory cytokines TNF-α and IL-6 were also significantly suppressed (Figure 2), suggesting Dlg1 By targeting NF-κB and MAPK pathways, it participates in the activation of microglia and its mediated inflammation, which may partly depend on potassium channel activity
.
Figure 2 Dlg1 regulates the NF-κB signaling pathway in microglia (picture quoted from: Z Peng, et al.
, Neurosci Bull 2021) Since Dlg1 gene knockout significantly reduces the inflammatory response of microglia, the researchers Try to explore the role of Dlg1 in inflammation-induced depression
.
The researchers first established mice (Dlg1flox/flox; CX3CR1CreER, referred to as cKO mice) that could induce microglial cell-specific Dlg1 gene knockout, and used tamoxifen to induce Cre recombinase activity in microglial cells.
To achieve the purpose of knocking out Dlg1
.
Then LPS (1mg/kg) was injected intraperitoneally to induce depression-like behavior in mice
.
The analysis of the behavioral test results of mine test, elevated plus maze, tail suspension test, and forced swimming test found that the lack of microglia Dlg1 can reduce inflammation-induced depression-like behavior in mice (Figure 3)
.
Figure 3 Knockout of Dlg1 gene in microglia can alleviate depression-like behaviors in mice induced by LPS (picture quoted from: Z Peng, et al.
, Neurosci Bull 2021) The morphology and number of microglia in the brain were studied, and the results of immunofluorescence and immunohistochemical staining showed that the Dlg1 gene knockout of microglia significantly saved the number and length of microglia branches induced by LPS.
Decrease and increase in cell body area
.
In addition, LPS injection increased the number of microglia in the hippocampus of control mice, while Dlg1 conditional gene knockout of microglia significantly reduced this increase (Figure 4)
.
These results indicate that the Dlg1 gene knockout in microglia significantly inhibits the activation of microglia in the mouse brain
.
Figure 4 Knockout of Dlg1 gene in microglia prevents the activation of microglia in vivo (picture quoted from: Z Peng, et al.
, Neurosci Bull 2021) Finally, the researchers analyzed iNOS, IBA1 and GFAP proteins in mouse hippocampus The protein levels of iNOS and IBA1 in cKO mice were significantly reduced under the stimulation of LPS, and the levels of GFAP decreased compared with control mice.
Inflammation of cKO mice Sex cytokines TNF-α and IL-6 were significantly reduced, and IL-1β levels showed a downward trend (Figure 5)
.
Together, these results indicate that the conditional deletion of Dlg1 by microglia inhibits the activation of microglia, thereby reducing depression-like behaviors caused by neuroinflammation
.
Figure 5 Knockout of Dlg1 gene in microglia can reduce inflammation in the brain of mice (picture quoted from: Z Peng, et al.
, Neurosci Bull 2021) Conclusion and discussion, inspiration and prospects of the article In summary, the study shows Knockout of Dlg1 gene inhibits the activation of NF-κB signal and MAPK pathway in microglia, thereby reducing the activation of microglia and the release of pro-inflammatory cytokines
.
In addition, the deletion of Dlg1 gene in microglia can alleviate depression-like symptoms in mice induced by inflammation
.
At the same time, the relationship between Dlg1 and potassium channel activity in this study is not clear, and whether it plays a synergistic effect in the disease process still needs further research
.
In conclusion, this study reveals the important role of Dlg1 in the activation of microglia and provides a potential therapeutic target for the treatment of depression
.
Original link: https://doi.
org/10.
1007/s12264-021-00765-x The corresponding author of this paper is Associate Professor Cheng Jinbo of Minzu University of China, and Researcher Yuan Zengqiang of the Academy of Military Medicine
.
The first author is Peng Zhixin from Nanhua University and Dr.
Li Xiaoheng from the Academy of Military Medicine
.
This work was greatly helped by Professor Liu Wanli of Tsinghua University
.
This work was jointly funded by key projects of the National Natural Science Foundation of China and general projects
.
Selected articles from previous issues [1] JAMA Neurol︱ Attention! Young people are more likely to suffer from "Alzheimer's disease"? [2] Brain | For the first time! PAX6 may be a key factor in the pathogenesis of Alzheimer's disease and a new therapeutic target [3] Sci Adv︱ blockbuster! DNA methylation protein DNMT1 mutation can induce neurodegenerative diseases [4] Cell︱ new discovery! New enlightenment of midbrain-regulated movement phenomenon for the treatment of Parkinson’s disease [5] Cereb Cortex︱MET tyrosine kinase signal transduction timing abnormality is a key mechanism affecting the development and behavior of normal cortical neural circuits in mice [6] Nat Biomed Eng︱ The team of academician Ye Yuru develops a new strategy for whole-brain gene editing-mediated treatment of Alzheimer's disease [7] Luo Liqun Science's heavy review System interpretation ︱ Neural circuit structure-a system that makes the brain "computer" run at high speed [8] Sci Adv ︱Important discovery! The calcium homeostasis regulatory protein Calhm2 regulates the activation of microglia and participates in the process of Alzheimer's disease [9] EMBO J︱ new discovery! AGHGAP11B promotes the expansion of the neocortex into adulthood and improves cognitive ability [10] Cell Death Differ︱ Qi Yitao/Wu Hongmei and others cooperate to reveal the molecular mechanism of SUMO modification regulating neurogenesis in adult mice [11] Cereb Cortex︱A2A receptor antagonist can Reversal of sequence learning impairment induced by abnormal aggregation of α-Syn (slide up and down to view) [1] ANDRADE L, CARAVEO-ANDUAGA JJ, BERGLUND P, et al.
The epidemiology of major depressive episodes: results from the International Consortium of Psychiatric Epidemiology (ICPE) Surveys [J].
International journal of methods in psychiatric research, 2003, 12(1): 3-21.
【2】CHENG AT, CHEN TH, CHEN CC, et al.
